Non-standard proteins in the lenses of AlphaFold3 - case study of amyloids

The recent release of AlphaFold3 raises a question about its powers and limitations. Here, we analyze the potential of AlphaFold3 for correct reproduction of amyloid structures, which are an example of multimeric proteins with low representation in protein structure databases, which may also be characterized by polymorphism. We show that AlphaFold3 is capable of producing amyloid-like assemblies that have significant similarity to experimental structures (TM-score>0.5), although its results are impacted by the number of monomers forming the predicted fibril and a protein of choice. AlphaFold3 produces structurally diverse models of some amyloid proteins, which could reflect their polymorphism observed in nature. We hypothesize that the lower emphasis on multiple sequence analysis (MSA) in AlphaFold3 improves the results quality, since for this class of proteins sequence homology may be misleading in their structural similarity. However, the structural landscape obtained from the modeling does not reflect the real one governed by thermodynamics. Finally, AlphaFold3 enables for the first time, structural modeling of fibril-like structures to a certain extent, possibly including their polymorphic nature. Still individual benchmarking is necessary for optimal modeling.